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rs80359013

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.7878G>A(p.Trp2626Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

BRCA2
NM_000059.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic reviewed by expert panel P:14U:1

Conservation

PhyloP100: 9.89
Variant links:
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32362595-G-A is Pathogenic according to our data. Variant chr13-32362595-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38124.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32362595-G-A is described in Lovd as [Pathogenic]. Variant chr13-32362595-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRCA2NM_000059.4 linkuse as main transcriptc.7878G>A p.Trp2626Ter stop_gained 17/27 ENST00000380152.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRCA2ENST00000380152.8 linkuse as main transcriptc.7878G>A p.Trp2626Ter stop_gained 17/275 NM_000059.4 A2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:14Uncertain:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria providedclinical testingSharing Clinical Reports Project (SCRP)Mar 12, 2013- -
Pathogenic, criteria provided, single submitterclinical testingCounsylSep 07, 2016- -
Pathogenic, criteria provided, single submitterclinical testingConsortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of CambridgeOct 02, 2015- -
Uncertain significance, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA2)Feb 20, 2013- -
Pathogenic, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Sep 08, 2016Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 29, 2023This sequence change creates a premature translational stop signal (p.Trp2626*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 21218378, 22970155, 25452441, 26187060). This variant is also known as 8106G>A. ClinVar contains an entry for this variant (Variation ID: 38124). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedresearchResearch Molecular Genetics Laboratory, Women's College Hospital, University of TorontoJan 31, 2014- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 07, 2023Variant summary: BRCA2 c.7878G>A (p.Trp2626X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251276 control chromosomes. c.7878G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Carney_2010, Kwong_2012, Couch_2015, Hondow_2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21702907, 21218378, 22970155, 25452441). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 15, 2019- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 24, 2023Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in individuals with personal or family history of breast and/or ovarian cancer (Carney et al., 2010; Kwong et al., 2012; Couch et al., 2015; Ow et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 30093976, 29487695, 29937436, 28888541, 21702907, 21218378, 26187060, 27157322, 22970155, 25452441, 32467295, 30702160, 29446198, 30787465, 33858678, 34022715, 25085752, 32091409, Huang_2021_Case Report, 30875412, 31825140) -
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthAug 22, 2022This variant changes 1 nucleotide in exon 17 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in at least 10 individuals affected with breast cancer (PMID: 21218378, 25452441, 26187060, 33471991; Color internal data; Leiden Open Variation Database DB-ID BRCA2_005264) and one proband who also had cancer of the brain (PMID: 21218378). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2022The p.W2626* pathogenic mutation (also known as c.7878G>A) located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7878. This changes the amino acid from a tryptophan to a stop codon within coding exon 16. This alteration has been reported in multiple high-risk breast and/or ovarian cancer patients in the literature (Carney ME et al. Hawaii Med J. 2010 Nov;69:268-71; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
BRCA2-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesAug 14, 2023The BRCA2 c.7878G>A variant is predicted to result in premature protein termination (p.Trp2626*). This variant has been reported in several individuals with a personal and/or family history of breast and/or ovarian cancer (see for example, Lilyquist J et al 2017. PubMed ID: 28888541; Kwong A et al 2015. PubMed ID: 26187060; Couch FJ et al 2014. PubMed ID: 25452441; Carney ME et al 2010. PubMed ID: 21218378; Kwong A et al 2012. PubMed ID: 22970155). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare in the general population. Nonsense variants in BRCA2 are expected to be pathogenic. This variant is classified as pathogenic by several submitters in ClinVar, including by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/38124/). This variant is interpreted as pathogenic. -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The BRCA2 p.Trp2626X variant was identified in 6 of 1438 proband chromosomes (frequency: 0.004) from multiethnic Asian individuals or families with high risk breast cancer; the variant being frequent in the Hong Kong population (Kwong 2012, Kwong 2015). The variant was also identified in dbSNP (ID: rs80359013) “With Pathogenic” allele, ClinVar (classified as pathogenic, reviewed by expert panel; submitters: ENIGMA, Counsyl, Invitae, Ambry Genetics, GeneDx, SCRP and CIMBA), Clinvitae (4x), BIC Database (1x, with unknown clinical importance, class 3-uncertain significance), and ARUP Laboratories (5-definitely pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The variant was also identified by our laboratory in 3 individuals at risk of familial breast cancer. The p.Trp2626X variant leads to a premature stop codon at position 2626, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 09, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
Cadd
Pathogenic
46
Dann
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.96
FATHMM_MKL
Pathogenic
0.97
D
MutationTaster
Benign
1.0
A;A
Vest4
0.87
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80359013; hg19: chr13-32936732; API